SK297692A3 - Imidazolylpropene acid substituted derivatives - Google Patents

Abstract

The substituted imidazolylpropenoic acid derivatives of the general formula (I) <IMAGE> can be prepared by reaction of the corresponding aldehydes with CH-acidic compounds and subsequent elimination of water. The substituted imidazolylpropenoic acid derivatives can be employed as active compounds in medicaments, in particular in hypotensive and anti-atherosclerotic medicaments.

Description

Technology «

The invention relates to novel substituted imidazolyl-propenoic acid derivatives, to a process for their preparation and to their use in medicaments, in particular as a blood pressure lowering agent and antisclerotic agents.

BACKGROUND OF THE INVENTION

The proteolytic enzyme renin is known to cleave in vivo from angiotensinogen the decapeptide angiotensin I, which in turn is broken down into blood pressure-increasing angiotensin-sin II octapeptide in the lungs, kidneys or other tissues. Various effects of angiotensin II, such as vasoconstriction, Na ⁺ -retention in the kidneys, aldosterone release in the adrenal glands, and an increase in sympathetic nervous system tension, act synergistically in terms of elevated blood pressure.

In addition, angiotensin II has the ability to increase the growth and multiplication of cells, such as heart muscle and smooth muscle cells, which, in various disease states (e.g., hypertonia, arthrosclerosis and cardiac insufficiency), grow and grow more.

Inhibition of renin activity by suppressing the activity of the angiotensin conversion system (ACE) as well as blocking the Angiotensin II receptor seems to be a possible intervention in the renin-angiotensin system (RAS).

EP 324 377, EP 403 158 A2 and EP 403 159 A2 disclose phenyl (alkyl) imidazole acids and imidazolalenic acids wherein the range of meaning at position 2 (see compounds of the invention -CH = CH-CO ₂ R 4) includes propenoic acids and their esters and the terminal phenyl ring is substituted with a tetrazole ring without giving any reference to a particular representative of this substitution pattern.

SUMMARY OF THE INVENTION

The present invention relates to substituted imidazolyl-propenoic acid derivatives of the general formula I

in which each denotes a straight or branched alkyl or alkenyl group having up to 3 carbon atoms each optionally substituted by a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, cyano, trifluoromethyl, trifluoromethoxy or pentafluoroethyl, or a straight or branched alkyl group of up to 6 carbon atoms, or an aryl group of 6 to 10 carbon atoms, a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms, or aryl 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocycle with up to 4 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen, optionally substituted up to three times the same or different halogen, hydroxy, nitro, cyano, trifl a fluoromethyl group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group each having up to 8 carbon atoms

atoms or a group of formula

-NR ⁸ R ⁹ , wherein

R and R are the same or different and are a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group, a "hydrogen atom", a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group,

6

R and R are the same or different and denote a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxyxupine or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms and r7 a hydrogen atom or straight or branched alkyl group up to 6 carbon atoms, and salts thereof.

Substituted imidazolyl-propenoic acid derivatives may also exist in the form of their salts. In general, they are salts thereof with organic or inorganic acids or bases.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of the substituted imidazolylpropenoic acid derivatives of the present invention include salts with mineral acids, carboxylic acids, or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumic acid. , maleic acid or benzoic acid.

Physiologically acceptable salts also include the metal and ammonium salts of the compounds of the present invention having a free carboxyl group. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds of the present invention may exist in stereoisomeric forms, which behave either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The present invention relates to both diastereomers or enantiomers as well as their respective mixtures. Racemic mixtures can be resolved into the stereoisomeric unitary constituents in a manner known per se (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962) by known methods.

Heterocycle denotes a generally 5- to 7-membered, preferably 5-membered and 6-membered, saturated or unsaturated ring which may contain up to 2 oxygen, sulfur and / or nitrogen atoms as heteroatoms. Five-membered and six-membered rings with oxygen, sulfur and / or up to two nitrogen atoms are preferred. Like. preference is given to thienyl, furyl, pyrrolyl, pyrazolvl, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrolidinyl, piperidinyl, piperazinyl or tetrazolyl.

Preferred are the compounds of formula I in which they denote

R ¹ represents straight-chain or branched alkyl or alkenyl each having up to 5 carbon atomv which are optionally substituted by cyclopropyl, cyclobutyl, cyclo pentyl or cyclohexyl, or represents cyclopropyl, cyclopentyl or a group of the cyclohexyl group,

R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, a trifluoromethoxy group, a pentafluoroethyl group, a phenyl group or a straight or branched alkyl group having up to 6 carbon atoms,

R is a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, or

Ί phenyl, furyl, thienyl, imidazolyl, pyrryl or pyridyl, optionally substituted up to twice the same or differently with fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl or trifluoromethoxy or propyloxy; a branched alkyl or alkoxy group each having up to 6 carbon atoms or a group of the formula

-nr ⁸ y ^with 3 9

R and R are the same or different and represent a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms,

R1 is a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms,

R ⁵ and R ⁶ are the same or different and denote a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a trifluoromethoxy group or a straight or branched alkyl group having up to 4 carbon atoms and a hydrogen atom or straight or branched alkyl group having up to And their salts.

Particularly preferred are the compounds of formula I in which they are

R 'is a straight or branched alkyl or alkenyl group having up to 4 carbon atoms or a cyclopropyl group, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine, a trifluoromethyl group, a pentafluoroethyl group, a phenyl group or a straight or branched alkyl group Or a phenyl, furyl or thienyl group optionally substituted by a fluorine atom, a chlorine atom, a cyano group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group or a propyl or propyl group; a branched alkyl or alkoxy group each having up to 4 carbon atoms or a group of the formula

-NR ^S R ⁹ in which it represents 8 3

R and R which are the same or different, a hydrogen atom, a methyl or ethyl group, a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms,

6

R and R are the same or different and denote a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom and

R is hydrogen, methyl, ethyl or propyl, and salts thereof.

Very particularly preferred are the compounds of formula I in which they are

· R ¹ represents straight-chain or branched alkyl or alkenyl having in each case up to 4 carbon atoms,

R is a hydrogen atom, a fluorine atom, a chlorine atom, an iodine atom, a trifluoromethyl group or a pentafluoroethyl group,

Fp a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, or a phenyl, furyl or thienyl group optionally substituted by a fluorine atom, a chlorine atom, a cyano or a methoxy group, d

R * is hydrogen, methyl or ethyl; and

6 7

R, R and R are hydrogen, and salts thereof.

In · · · * ·· *

The present invention further provides a process for the preparation of the compounds of the formula I according to the invention and their salts, which comprises the use of aldehydes of the formula II:

,. . In which may R, R first carry out the reaction

5, R and R are as defined above, with compounds of formula

III r ³ - (CH ₂ ) ₉ -co ₂ r ¹⁰ (III), in which R is as defined above for ag, 4

R is as defined above for R but does not represent a hydrogen atom, in an inert solvent and in the presence of a base, to the compounds of formula IV

then the free hydroxyl functions are blocked by introducing protecting groups and, in the final step, excretion is carried out in an inert solvent in the presence of a base, and in the case of acids (R = H) the esters are saponified and R is not hydrogen. atom, the -NH function is alkylated.

The following reaction scheme illustrates the process of the present invention.

Hydroxy protecting groups within the above definition are general protecting groups selected from the group consisting of benzyloxycarbonyl, methanesulfonyl, toluenesulfonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl. a group, allyloxycarbonyl, 4-methoxycarbonyl, acetyl, trichloroacetyl,

2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 2- (methylthiomethoxy) ethoxycarbonyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl group. Acetyl, methanesulfonyl and toluenesulfonyl are preferred.

Suitable solvents for this process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane and beet fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene and chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Mixtures of the abovementioned solvents may also be used. Tetrahydrofuran, methylene chloride and toluene are preferred for the various steps.

In general, inorganic or organic bases can be used as bases for the process according to the invention. These include, in particular, alkali metal hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as carbonate calcium, alkali metal or alkaline earth metal alcoholates or amides thereof, such as sodium or potassium ethanolate, potassium tert-butylate or lithium diisopropylamide (LDA), organic amines (trialkyl (C 1 -C 8) amines), such as triethylamine, heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine . However, it is also possible to use alkali metals such as sodium or hydrides thereof such as sodium hydride as bases. Lithium diisopropylamide (LDA) and DBU are preferred.

In general, the bases are used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, based on 1 mol of the compound of formula III.

The process of the present invention is generally carried out at a temperature in the range of -100 to 100 ° C, preferably at -78 ° C.

The process of the present invention is usually carried out at normal pressure. However, it is also possible to operate at elevated or reduced pressure (for example in the range of 0.05 to 0.5 MPa).

The deprotection is usually carried out in one of the abovementioned solvents and in the presence of a base, preferably methylene chloride with dimethylaminopyridine.

The blocking is generally carried out at a temperature in the range of 0 to 60 ° C, preferably at room temperature and under normal pressure.

Elimination is usually carried out in one of the above solvents, preferably toluene, and in the presence of one of the abovementioned bases, preferably DBU.

Elimination is generally carried out at a temperature in the range of 30 to 130 ° C, preferably at 50 to 100 ° C and at normal pressure.

Suitable bases are the inorganic bases customary for saponification. These preferably include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium ethanolate, sodium methoxide, potassium ethoxide, potassium methoxide or potassium tert-butylate. Sodium or potassium hydroxide is particularly preferred.

Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis. X preferably includes alcohols such as methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol, ethers such as tetrahydrofuran or dioxane, and dimethylformamide or dimethylsulfoxide. Particularly preferred are alcohols such as methanol, ethanol, propanol or isopropanol. Mixtures of the solvents mentioned may also be used.

The saponification can also be carried out with acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or phosphoric acid, with trifluoroacetic acid being preferred.

The saponification is usually carried out at a temperature in the range of 0 to 100 ° C, preferably in the range of 20 to 80 ° C.

Usually, the saponification is carried out at normal pressure, but it is also possible to work at reduced or elevated pressure (e.g., 0.5 to 5 bar).

In carrying out the saponification, the base is usually used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester. Particularly preferred are molar amounts of reactant.

In carrying out the reaction, the carboxylates of the compounds of the present invention are formed in the first step as intermediates which can be isolated. The acids of the present invention are obtained by treating the carboxylate with customary inorganic acids. This includes preferred mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. In the preparation of carboxylic acids, it has proven advantageous to acidify the basic reaction mixture in the second step without saponification of the carboxylate in the second step. The acids can then be isolated by conventional means. In the case of basic heterocycles, treatment of the carboxylate solution with the above acids can also yield heterocyclic salts with inorganic acids.

The alkylation is generally carried out with alkylating agents such as alkyl halides. C 1-6 carbon atoms, sulfonic acid esters, or substituted or unsubstituted dialkyl sulfonates having 1 to 6 carbon atoms or diarylsulfonates, preferably methyl iodide or dimethyl sulfate.

The alkylation is usually carried out in one of the abovementioned solvents, preferably dimethylformamide, at a temperature in the range of 0 to 70 ° C, preferably 0 to 30 ° C, and at elevated pressure.

The compounds of formula (II) are known per se or can be prepared by conventional methods (see, for example, PCT 17091/00277).

The compounds of formula III are known per se or can be prepared by known methods (see, for example, Beilstein 9, 511).

The compounds of formula (IV) are novel as specific representatives of the substance and can be prepared, for example, by the above processes.

The production processes described above are given for clarity only. The production of the compounds of the formula I according to the invention is not limited to the above process, any modification of the process being applicable in the same way.

The substituted imidazolyl-propenoic acid derivatives of the invention have an unpredictable valuable spectrum of pharmacological activity.

The compounds of the present invention have a specific A II-antagonistic effect since they competitively inhibit the binding of angiotensin II to receptors. They suppress vasoconstrictor effects and effects that stimulate aldosterone secretion in angiotensin II. In addition, they inhibit the proliferation of smooth muscle cells.

They can therefore be used in medicaments for application in artherial hypertonia and atherosclerosis. In addition, they can be used for coronary heart disease, cardiac insufficiency, cerebral blood flow disorders, leg ischemic disorders, peripheral blood circulation disorders, renal and adrenal function disorders, bronchospastic and vascular-related respiratory diseases, sodium retention and swelling.

Determination of inhibition of antagonist-induced contractions

Rabbits of both sexes are stunned by the back of the neck and exsanguinated, or possibly anesthetized with Nembutal (about 60-80 mg / kg i.v.) and sacrificed by opening the thorax. Thoraxaorta is removed, rid of surrounding tissues, divided into annular elements about 1.5 mm wide and processed individually at an initial load of about

3.5 g in a 10 ml organ bath with Krebs-Henseleit nutrient solution treated with carbogen and tempered to 37 ° C with the following composition:

119 mmol / l 2.5 mmol / l 1.2 mmol / l 10 mmol / l 4.8 mmol / l 1.4 mmol / l 25 mmol / l sodium chloride calcium chloride dihydrate potassium dihydrogen phosphate glucose potassium chloride magnesium sulfate (heptahydrate ) and sodium bicarbonate.

Contractions are detected isometrically using a Statham UC2-Zellen via a must amplifier (ifd Mulheim or DSH Aalen, respectively) and digitized and evaluated! by the A / D-Wandler procedure (System 570, Keithley Minchen). The administration of agonist dose-response curves (DWK) is done. hour. For each DWK, 4 individual concentrations are added to the bath at the end of the DWK and the subsequent wash cycle (about 5 sec / min each with the above nutrient solution). A twenty-eight minute rest period or an incubation phase during which the contractions generally reach the baseline.

apply a 3 or 4 minute interval,

Normally, the height of the 3rd DWK is used as a comparative value to evaluate the test substances tested in other experiments, which are applied at successive DWKs in ascending doses to the bath at the beginning of the incubation period. Each aortic ring is always stimulated with the same antagonist all day.

Antagonists and their standard concentrations (application volume for single dose = 100 µl):

KC1. 22.7; 32.7; 42.7; 52.7 mmol / 1 L-noradrenaline 3 x 10 'g / ml 9 -7; 3 x 10 ^z ; 3 x io ' ⁶ serotonin 10 ⁸ ; 10 ~ ⁷ ; 10 ^_6 ; 1θ "° g / ml B-HT 920 10 ' ⁷ _? -7 1θ ' ^δ · 10 ~ ⁵ g / ml -6 -5 methoxamine 10; 10; 10 g / ml angiotensin II 3 x 10 g / ml. ⁹ ; 10 '⁸; 3 x 10 ~ ⁸ ; 10 ' ⁷ for value calculation IC ₅₀ (concentration, at which tested substance causes 50% inhibition) with takes as basis effect always on 3. = submaximal concen-

traci antagonist.

The compounds of the present invention inhibit dose-dependent angiotensin II induced contractions of isolated aortic rabbit. Contractions induced by potassium depolarization or other antagonists were not inhibited at all or only slightly at high concentrations.

Measurement of blood pressure in rats infused with angiotensin II

Male Wistar rats (Moellegraad, Kopenhagen, Dänemark) weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a catheter for measuring blood pressure is inserted into the femoralartery and a catheter for infusing angiotensin II and a catheter for administering the substance are introduced into the femoralvena. After administration of pentolinium (5 mg / kg i.v.), a ganglia blocking agent, an angiotensin II infusion (0.3 µg / kg / min) is started. Once the blood pressure has reached a stable level, the test substances are applied either intravenously or orally as a suspension or solution in 0.5% Tylose. Changes in blood pressure due to test substances are shown in the table as mean values - SEM.

Determination of antihypertensive effect in waking hypertensive rats

The oral antihypertensive effect of the compounds of the present invention was tested in waking rats with surgically induced unilateral renal arterienstenosis. To do this, the right kidney artery was narrowed with a silver clip to a clear width of 0.13 mm. In this form of hypertonia, plasma renin activity is increased in the first six weeks after the procedure. The arterial blood pressure of these animals was measured at defined times after administration of the substance bloodless by the tail cuff. The test substances are administered in varying doses ranging in the tylosis suspension by intra-gastrointestinal (oral) gavage. The compounds of the present invention reduce the arterial blood pressure of hypertensive rats at clinically relevant doses.

In addition, the compounds of the present invention inhibit concentration-specific binding of radioactive angiotensin II in a concentration-dependent manner.

Interactions of the compounds of the present invention with angiotensin II receptors on the membrane fractions of the bovine adrenal cure

The bovine adrenal (NNR) cure, which was freshly removed and shed the remainder of the capsule, was ground in a sucrose solution (0.32 M) with Ultra-Thorax (Janke & Kunkel, Staufen iB) to a coarse membrane homogenate and in two centrifugation steps. partial divided into membrane fractions.

Receptor binding is investigated on the partially purified bovine NNR membrane fractions of radioactive angiotensin II in a 0.25 ml assay volume containing individual partially purified membranes (50-30 µg), ³ H-angiotensin II (3-5 nM) , buffer solution (50 mM Tris, pH 7.2, 5 mM MgCl 2, 0.25%

BSA) as well as the test substance. After an incubation time of 60 minutes at room temperature, unbound sample activity is separated by a moistened glass fiber filter (Whatman GF / C) and the bound radioactivity is washed after washing the protein with ice buffer (50 mM Tris / HCl, pH 7.4, 5%). PEG 6000) is measured spectrophotometrically in a scintillation cocktail. The analysis of the raw data is carried out using computer programs to give K, optionally IC - "(K: the IC ^ _n corrected for the ^{radioactivity,:} concentration at which the substance under investigation causes 50% inhibition of total binding of the radioligand).

Smooth muscle cell proliferation inhibition assay by compounds of the invention

Smooth muscle cells obtained from the aorta of rats by the Media-Lplantat technique (R. Ross, J. Cell Biol. 50, 172, 1971) were used to determine the antiproliferative effect of the compounds. Cells are plated in suitable culture dishes, typically on 24-well trays, and cultured in 199 (7.5%) medium for 2-3 days.

FCS and 7.5% NCS, 2 mM L-glutamine and 15 mM HEPES, pH

7.4 in 5% CO _? ) at 37 ° C. The cells are then withdrawn from the serum. for 2 to 3 days, they synchronize and eventually activate A II, serum or other factors to grow. At the same time, test compounds are added. After 16-20 hours, 1 µCi of H-thymidine was added and after a further 4 hours the incorporation of this substance into TCA-precipitable DNA cells was determined.

The novel compounds of the present invention can be converted into conventional formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, by known methods, using inert, non-toxic and pharmaceutically acceptable carriers or diluents. The therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight, based on the total mixture, i.e. in an amount sufficient to achieve the level indicated.

For example, the formulations may be prepared by mixing the active ingredient with a solvent and / or carrier, optionally using emulsifying agents and / or dispersing agents, whereby, for example, if water is used as a surfactant, an organic solvent may optionally be used as an excipient.

Administration is effected by conventional means, in particular orally or parenterally, in particular perlingually or intravenously.

For parenteral administration, solutions of the active ingredient using suitable liquid carrier materials may be employed.

In general, it has proven advantageous to use an amount of active compound of about 0.001 to 1 mg / kg, in particular 0.01 to 0.5 mg / kg of body weight, for intravenous administration in order to obtain effective results. When administered orally, this dose is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to withdraw from the indicated amounts, depending on body weight, the type of administration, the individual behavior towards the medicament, the type of formulation and the moment or the interval of administration. Thus, in some cases it may be sufficient to start from less than the minimum amounts mentioned above, while in other cases the upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide the dose into a larger number of individual doses over the day.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

P. Example i

2-Benzyl-3- [2-n-butyl-4-chloro-1 - [(2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazole methyl ester 5-yl / -3-hydroxy-propionic acid

180.4 mg (1.1 mmol) of methyl 3-phenylpropionate are dissolved in 2 ml of tetrahydrofuran and then 0.8 ml of a 1.5 M solution of lithium diisopropylamide in cyclohexane27 (1 ml) is added at -78 ° C. 2 mmol). The reaction mixture was stirred for 30 minutes at -78 ° C, then 662.5 mg (1.0 mmol) of 2-n-butyl-4-chloro-1- / 2 '- (N-triphenylmethyl) was added. 1-Etrazol-5-yl) -phenyl] -1H-imidazole-5-carboxaldehyde in 5 ml of tetrahydrofuran and stirred for a further 30 minutes at -78 ° C. At 0 ° C, 5 mL of saturated ammonium chloride solution was added and extracted three times with 20 mL of diethyl ether. The organic phase is dried over anhydrous sodium sulphate and the residue is chromatographed over silica gel 60 using a 1: 1 mixture of ethyl acetate and petroleum ether,

Yield: 300 mg (36% of theory)

R1 = 0.53 and 0.48 mixture of diastereomer (ethyl acetate / petroleum ether 1: 1).

Example II

(E) -2-Benzyl-3- [2-n-butyl-4-chloro-1 - [(2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl) -methyl] -methyl] - 1 H -imidazol-5-yl, 2-propene

co ₂ ch ₃ (C ₆ H 5) ₃ c

300 mg (0.36 mmol) of the compound of Example I was dissolved in 3 mL of dichloromethane and then 16 mg (0.13 mmol) of N, N-dimethylaminopyridine (DAI'IP) and 41 mg (0.4 mmol) were added sequentially. acetic anhydride. The reaction mixture was stirred for 1 hour at 25 ° C and 2 ml of water and 10 ml of diethyl ether were added. The organic phase is extracted successively with 3 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product thus obtained was dissolved in 3 ml of toluene and 183 mg (1.2 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added and stirred for 20 hours at 90 °. C. After cooling, 3 ml of diethyl ether are added, extracted with 5 ml of saturated sodium chloride solution, the organic phase is concentrated and the residue is chromatographed on silica gel 60 using a mixture of ethyl acetate and petroleum ether (1: 2).

Yield: 120 mg (41% of theory)

Rf = 0.63 (ethyl acetate / petroleum ether 1: 1).

Example III

(E) -3- [2-n-Butyl-4-chloro-1 - [(2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazole-5- ethyl ester yl / -2- (2-methylpropyl) -2-propenoic acid

Analogously to Example II, the title compound was prepared from 1.72 g (2.13 mmol) of 3- / 2-n-butyl-4-chloro-1 - [(2 '- (N-triphenylmethyltetrazole) ethyl ester). 5-y1) biphenyl-4-y1) methyl / -1 H-imidazol-5-yl / -3-hydroxy-2- (2-methylpropyl) -2-propenoic acid

Yield: 440 mg (27% of theory)

Rf = 0.71 (ethyl acetate / petroleum ether 1: 2).

Example IV

2-n-butyl-1 - / (2 &apos; N-triphenylmethyl-tetrazol-5-y1 / y1-bifeny1-4) methyl / -lH-imidazole-5-carboxaldehyde

A solution of 12.0 g (18.1 mmol) of 2-n-butyl-4-chloro-1 - [(2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazole Of 5-carboxaldehyde in 150 ml of methyl alcohol 25 C in the presence of 2.46 g (18.1 mmol) under hydrogen pressure for three.5 hours at a temperature of

1.2 g of palladium on carbon (5%) and sodium acetate hydrate for about 0.3 MPa. The catalyst is then filtered off, concentrated and the residue is chromatographed on silica gel using a 1: 1 mixture of ethyl acetate and petroleum ether.

Yield: 3.85 g (34% of theory)

Rf = 0.41 (ethyl acetate / petroleum ether 1: 1).

Example V

3- (2-n-Butyl-1 - [(2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl] -2- (2) ethyl ester methoxypropyl) 3-hydroxy-propionic acid

To a solution of 0.89 g (8.75 mmol) of Ν, Ν-diisopropylamine in 10 ml of tetrahydrofuran, 5.15 ml (8.25 mmol) was injected under a protective gas atmosphere at -78 ° C.

Of a 1.6 N solution of n-butyllithium in n-hexane. The reaction solution was then briefly warmed to 0 ° C, re-cooled to -78 ° C, and 1.24 mL (7.5 mmol) of isocaproic acid ethyl ester in 5 mL of tetrahydrofuran was added. The reaction mixture was stirred for 30 minutes _in VO. x at -78 ° C, and then 3.14 g (5 mmol) of the compound of Example IV in 20 mL of tetrahydrofuran was added and further stirred at -78 ° C for one hour. It is then slowly warmed to 25 ° C, 20 ml of saturated ammonium chloride solution are added and extracted three times with 50 ml of ethyl acetate each time. The organic phase is dried over anhydrous sodium sulphate, concentrated and the residue is purified on silica gel with a 3: 1 mixture of ethyl acetate and petroleum ether.

Yield: 1.82 g (47% of theory). Rf = 0.27 (ethyl acetate / petroleum ether 2: 1, mixture of diastereomers)

Example VI

3-Acetoxy-3- (2-n-butyl-1 - [(2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazole-5 ethyl ester yl / 2- (2-propylmethyl) -propionic

11.1 g (14.4 mmol) of the compound of Example V are dissolved in 100 ml of dichloromethane, mixed with 525 mg (5.13 mmol) of N, N'-dimethylaminopyridine (DMAP) and 2.04 ml (21.5 mmol). The reaction mixture was stirred for 15 hours at 25 ° C and then diluted with dimethyl ether, washed with water (1 x 50 mL), saturated sodium bicarbonate solution (1 x 50 mL) and saturated sodium chloride solution (1 x 50 mL). The organic phase is dried over sodium sulphate and concentrated, and the crude product is chromatographed on silica gel with a 2: 1 mixture of ethyl acetate and petroleum ether.

Yield: 11.7 g (100% of theory)

Rf = 0.52 (ethyl acetate / petroleum ether 2: 1, mixture of diastereomer).

Example VII

3- (2-n-Butyl-1- [2 '- (N-triphenylmethyl tetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl] -2- (2- methylpropyl) -2-propenoic acid

11.7 g (14.3 mmol) of the compound of Example VI are dissolved in 150 ml of toluene, 5.3 ml (35.8 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) are added. ) and stirred for 5 hours while heating under reflux. Then 2 ml (13.5 mmol) of DBU are added again and refluxed for 2.5 hours. After cooling, it is washed with a saturated sodium chloride solution (1 x 70 ml), the organic phase is dried over sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel with ethyl acetate / petroleum ether (1: 1).

Yield: 3 g (28% of theory)

FU = 0.68 (ethyl acetate / petroleum ether)

1).

Production examples

Example 1

(E) -2-Benzyl-3- [2-n-butyl-4-chloro-1 - [(2 '- (tetraazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazole- 5-yl / 2-propenoic acid

mg (0.1 mmol) of the compound of Example II is dissolved in 3 ml of 2 N methanolic sodium hydroxide, heated to boiling for 30 minutes, acidified with concentrated hydrochloric acid to pH 1 after cooling, and extracted with 20 ml of dichloromethane .

After concentration, the residue is chromatographed on silica gel 60 using dichloromethane / methanol / glacial acetic acid (10: 1: 0.05).

Yield: 37 mg (67% of theory) = 0.40 (dichloromethane / methanol / ice / acetic acid 10: 1: 0.05).

Example 2

(E) -3- [2-n-Butyl-4-chloro-1 - [(2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl] -4-imidazol-5-yl] - 2- (4-methoxybenzyl) -2-propenoic acid

To a solution of 3- (2-n-butyl-4-chloro-1 - [(2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) biphenyl-4-yl) methyl] methyl ester 355 mg (0.42 mmol) 1H-Imidazol-5-yl] -2- (4-methoxybenzyl) -2-propenoic acid in 6 ml of tetrahydrofuran was added with 2 ml of water and 2 ml of trifluoroacetic acid. The reaction mixture was stirred for 6 hours at 25 ° C, concentrated, taken up in dioxane / water (1: 1) and basified with concentrated lithium hydroxide solution. The reaction mixture was stirred for 3 hours at room temperature

The aqueous phase was acidified with dilute hydrochloric acid and extracted again with ethyl acetate. The organic phases are dried over anhydrous sodium sulphate, concentrated and the residue is chromatographed on silica gel 50 using a mixture of dichloromethane and methanol (8: 1).

Yield: 230 mg (94% of theory)

R _x = 0.63 (dichloromethane / methanol 8: 1).

i.

Example 3

(E) -3- [2-n-Butyl-4-chloro-1 - [(2 '- (trazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl ethyl ester / 2- (2-methylpropyl) -2-propenoic acid

To a solution of 440 mg (0.56 mmol) of the compound of Example III in 10 mL of tetrahydrofuran was added successively 1.5 mL of water and 1.5 mL of trifluoroacetic acid. The reaction mixture was stirred for 24 hours at 25 ° C, basified with concentrated sodium hydroxide, washed with 20 ml of diethyl ether, the aqueous phase acidified with semi-concentrated hydrochloric acid and extracted three times with 30 ml of ethyl acetate each time. The organic phases are dried over anhydrous sodium sulphate, concentrated and the residue is chromatographed over silica gel 60 using a mixture of dichloromethane and methanol (10: 1).

Yield: 130 mg (43% of theory)

Rj. Melting point = 0.31 (dichloromethane / methanol 10: 1).

h

Example 4

(E) -3- [2-n-Butyl-4-chloro-1 - [(2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl] - 2- (2-thienylmethyl) -2-propenoic acid

Analogously to Example 1, the title compound was prepared from 410 mg (0.72 mmol) of (E) -3- / 2-n-butyl-4-chloro-1 - / (2'- (tetrazole) ethyl ester) (5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl- (2-thienylmethyl) -2-propene.

Yield: 110 mg (28% of theory)

Rf = 0.27 (dichloromethane / methanol 10: 1).

Example 5

3- (2-n-Butyl-1 - [(2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl] -2- (2-methylpropyl) ethyl ester ) -2-propene

A solution of 3.0 g (3.9 mmol) of the compound of Example VII in 30 ml of methanol was slowly treated with 2 ml of concentrated hydrochloric acid. After 15 minutes, the reaction solution is poured into 300 ml of water, extracted with dichloromethane (4 x 70 ml), the organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel using a mixture of toluene, methanol and glacial acid. acetic (35:

: 5: 0.5).

Yield: 1.88 g (94% of theory)

R.c = 0.21 (toluene, / methanol / glacial acetic acid 35):

: 5: 0.2).

Example 6

3- [2-n-butyl-1 - [(2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl] -1H-imidazol-5-yl] -2- (2-methylpropyl) - 2-propenoic acid

• l.

To a solution of 1.44 g (2.8 mmol) of the compound of Example 5 in 50 mL of methanol was added a solution of 1 g of sodium hydroxide in 10 mL of methanol, and the reaction mixture was stirred for 16 hours at 50 ° C.

After cooling, it is acidified with dilute hydrochloric acid, extracted with dichloromethane (3 x 75 ml) and ethyl acetate (3 x 75 ml), the combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated. The residue is chromatographed on silica gel with toluene / methanol / glacial acetic acid (35: 5: 0.2).

Yield: 0.41 g (30% of theory)

Rf = 0.12 (toluene / methanol / glacial acetic acid 35: 5: 0.2)

General procedure for salt production

A solution of the corresponding imidazolyl-propenoic acid in a mixture of dioxane and water was neutralized with an equimolar amount of 1 N sodium hydroxide, allowed to freeze and lyophilized overnight.

The compounds listed in Tables 1 and 2 are prepared analogously to the procedures described above.

table

Pr. . . R ² R ³ R ⁴ isomer Rf 7 Cl H (FROM) 0,32 ^b) 8 H -ch ₃ 0,18 ^c) 9 H /IN H 0.17 ^d > 10 H X H 0,19 ^a) 11 H XT H 0.15 ^{d) e)} K 12 H jX H 0.16 ^d > ir 13 H H 0,16 ^d) 14 H xr -ch ₃ 0.24 ^d >

(a) dichloromethane / methanol 10: 1

b) dichloromethane / methanol 5: 1

c) toluene / methanol / ice. acid. acetic acid 35: 5: 0.2

d) toluene / methanol / ice. acid. acetic acid 35: 5: 1

e) dichloromethane / methanol / ice. acid. acetic: 1: 0.05

Table 2

R ³

P r- ňr R ³ R ⁴ M 15 CH _{(CH3) 2} C ₂ H ₅ On the 16 CH _{(CH3) 2} On the On the 17 ch ₃ On the 18 / Q On the On the 19 xx ch ₃ On the 20 XX ' On the On the

Claims (9)

PATENT REQUIREMENTS in which: R ² represents straight-chain or branched alkyl or alkenyl having in each case up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms, hydrogen, halogen, hydroxy, nitro, cyano , trifluoromethyl, trifluoromethoxy or pentafluoroethyl, or a straight or branched alkyl group having up to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms, R is a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms, or an aryl group of 6 to 10 carbon atoms or a 5- to 7-membered saturated or unsaturated heterocycle of up to 4 heteroatoms selected from sulfur, nitrogen and oxygen optionally substituted up to three times the same or different halogen, hydroxy, nitro, nitro, cyano, trifluoromethyl, trifluoromethoxy or a straight or branched alkyl or alkoxy group of up to 8 carbon atoms or a group of the formula -NR ⁸ R ^{9 with} pr R ⁸ and R ⁹ are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group, R @ ^{1 is a} hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group; R and R are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each; R is a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, and salts thereof. Substituted imidazolyl-propenoic acid derivatives according to claim 1, in which R @ 1 denotes a straight or branched alkyl or alkenyl group of up to 6 carbon atoms each optionally substituted by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, or a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, a trifluoromethoxy group, a pentafluoroethyl group, a phenyl group or a straight or branched alkyl group having up to 6 carbon atoms, R is a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, or a phenyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrryl group or a pyridyl group, optionally substituted up to twice or equal to fluorine, chlorine, a bromine atom, a hydroxy group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms, or a group of the formula -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ R 1 of the hydrogen atoms are the same or different and denote a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, the atom or a straight or branched alkyl group having up to 6 carbon atoms, 5 6 R and R are the same or different and denote a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a trifluoromethoxy group or a straight or branched alkyl group having up to 4 carbon atoms, and R is a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, and salts thereof. ; · Νύ · 2; ΐ '^; -., 0, ••• M.s47 3. Substituted imidazolyl-propenoic acid derivatives according to claim 1, in which they denote R 'is a straight or branched alkyl or alkenyl group of up to 4 carbon atoms or cyclopropyl, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine, a trifluoromethyl group, a pentafluoroethyl group, a phenyl group or a straight or branched alkyl group Or a phenyl, furyl or thienyl group optionally substituted by a fluorine atom, a chlorine atom, a cyano group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group or a trifluoromethoxy group or a phenyl group alkyl or alkoxy having up to 4 carbon atoms in each case, or a group of formula -nr ⁸ r ⁹ , in which denotes 8 9, R and R which are the same or different, a hydrogen atom, a methyl or ethyl group, a hydrogen atom or a straight or branched chain An alkyl group having up to 4 carbon atoms, R and R are the same or different and denote a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom and R ^{2 is a} hydrogen atom, a methyl group, an ethyl group or a propyl group, and salts thereof. 4. Substituted imidazolyl-propenoic acid derivatives according to claim 1, in which they denote R is a straight or branched alkyl or alkenyl group with up to 4 carbon atoms in each case, 2 _x R hydrogen (ato, fluorine, chlorine, iodine, trifluoromethyl or pentafluoroethyl)) ABOUT ^Rj represents hydrogen or straight or branched alkyl having up to 4 carbon atoms, or a phenyl, furyl or thienyl group which is optionally substituted by fluo ru, chlorine, cyano or methoxy, R is hydrogen, methyl or ethyl; and R ^5, R a R ^Z represents hydrogen, the salts thereof. 6. A process for the preparation of a substituted imidazolyl-propenoic acid derivative of the formula I in which it represents a straight or branched alkyl or alkenyl group having up to 8 carbon atoms each optionally substituted by a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. up to 8 carbon atoms, R is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group or a pentafluoroethyl group, or a straight or branched alkyl group having up to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms, R ^{8 is a} hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms, or an aryl group of 6 to 10 carbon atoms, or a 5- to 7-membered saturated or unsaturated heterocycle of up to 4 heteroatoms selected from sulfur, nitrogen and oxygen; substituted up to three times the same or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or a straight or branched alkyl or alkoxy group of up to 8 carbon atoms or of the formula -NR ⁸ R ^{9 with} pr R ⁸ and R ⁹ are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group, R1 is a hydrogen atom, a straight or branched alkyl group having up to 8 carbon atoms, or a phenyl group, R ⁵ and R ⁵ are the same or different and denote a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each; and having salts thereof, characterized in that the aldehydes of formula II (II) in which R, R ² , R ³ and R 0 are as defined above are first reacted with compounds of formula III 3 10 R - (CH ₂ ) ₂ -CO ₂ R (III), wherein a is as defined above and R ¹ 0 is as defined above for R ^4, but does not represent hydrogen, in inert solvents and in the presence of a base, to Cpd Nina formula IV (IV) in which R ¹ Deny above, R ' R ' R ^10, above, free hydroxyl functions are blocked by introducing protecting groups and, in the final step, excretion is carried out in an inert solvent in the presence of a base, and in the case of acids and in case R ⁷ is alkylated. (R '= H) the esters are saponified, not a hydrogen atom, with -NH-funk. The method of claim 5, wherein the temperature is in the range of -100 to 100 ° C. 7. Substituted propenene according to claim imidazolyl acid derivatives for combating diseases. A medicament comprising at least one substituted imidazolyl-propenoic acid derivative according to claim 1. The medicament of claim 8 for the treatment of high blood pressure and atherosclerosis. Use of substituted imidazolyl-propenoic acid derivatives according to claim 1 for the manufacture of medicaments.